New findings suggest that a blood test can predict the transition from preclinical to clinical Alzheimer's disease.
Researchers have developed a new laboratory test that can measure levels of a “toxic” protein that is highly correlated with developing Alzheimer’s disease (AD) years before any symptoms of cognitive impairment appear. Published on December 5 in Proceedings of the National Academy of Sciences, the findings could be used to identify people at risk for AD, as well as help develop early treatments for the disease, according to researchers.
What clinicians and researchers have wanted is a reliable diagnostic test for Alzheimer’s disease — and not just one that confirms a diagnosis of Alzheimer’s, but a way to detect signs of the disease before cognitive impairment happens, says senior author Valerie Daggett, PhD, a professor of bioengineering in the University of Washington (UW) Molecular Engineering and Sciences Institute in Seattle.
“This disease touches lots of families — it’s just a matter of time until all of us are affected by it in some way,” says Dr. Daggett.
By 2050, the number of U.S. adults over 40 living with dementia is projected to rise from 5.2 million people to 10.5 million, according to an analysis published in January 2022 The Lancet. The study predicts that the number of people with dementia will go up in every country in the world, resulting in a near tripling in the global rate of dementia.
Over the past few years, scientists conducted much research on the presence of amyloid beta proteins in people with Alzheimer’s disease.
However, sometimes amyloid beta proteins can become corrupted and start to
Some previous research shows a correlation between amyloid plaques and Alzheimer’s disease. However, additional research emerged and presented conflicting findings against the amyloid plaque theory.
New Test Could Determine Who Needs Treatment and Who Can Have ‘Peace of Mind’
Most people receive a diagnosis of Alzheimer’s only after they develop signs of the disease, such as memory loss. But changes in the brain related to AD begin years before these signs appear — this is called preclinical Alzheimer’s disease, according the Alzheimer’s Association.
These findings suggest that this test can diagnose Alzheimer’s and accurately predict the transition from preclinical to clinical disease, says Martin Sadowski, MD, PhD, professor of neurology and psychiatry at the NYU Grossman School of Medicine and a neurologist who specializes in dementia and Alzheimer’s at NYU Langone Health, both in New York City. Dr. Sadowski was not involved in this research. “Hence it can tell apart who is at imminent risk of cognitive decline and who can have peace of mind,” he says.
The new test could provide an accessible way for people to find out if they have AD — and if they do have evidence of the toxic protein, they can begin taking any available treatments to slow down progression, as well as make important lifestyle modifications, says Daggett.
Sadowski agrees, saying, “People identified as at risk can be offered therapeutics delaying disease onset, [such as] lecanemab.”
For this study, researchers developed a laboratory test called SOBA (soluble oligomer binding assay) to detect amyloid beta protein oligomers in blood samples.
“It’s estimated that damage is being done to the brain for 10-20 years before the advent of symptoms,” stated Dr. Valerie Daggett, professor of bioengineering and faculty member in the Molecular Engineering & Sciences Institute at the University of Washington and senior author of this study.
“To be able to truly modify the course of the disease we need to intervene early when the toxic oligomers first begin attacking neurons, otherwise it’s like trying to treat stage 4 cancer.
Earlier is always better, but first, we need a blood-based diagnostic test that can detect the disease earlier and reliably at all stages.”
– Dr. Daggett
Dr. Daggett and her team used the new SOBA test on blood samples from 310 people already participating in Alzheimer’s research. When collecting blood samples, researchers classified participants as having no signs of cognitive impairment, MCI, Alzheimer’s disease, or another form of dementia.
The SOBA test found oligomers in the blood samples of people with MCI and moderate to severe Alzheimer’s disease. In 53 cases, an autopsy after death verified the Alzheimer’s diagnosis. And in 52 of those cases, toxic oligomers were found in their blood.
Although There Isn’t a Cure for AD, Potential Therapies and Lifestyle Changes May Improve Outcomes
Currently, there’s only one approved disease-modifying treatments for AD: aducanumab (Aduhelm). If Alzheimer’s could be detected earlier, that could pave the way for more treatments that could help slow down AD before irreparable damage occurs, according to the authors.
Although not yet approved by the U.S. Food and Drug Administration (FDA) to treat early AD, lecanemab is monoclonal antibody that appears to reduce markers of amyloid in early Alzheimer’s and resulted in moderately less decline on measures of cognition and function at 18 months compared with a placebo. The findings were published on November 29, 2022, in The New England Journal of Medicine.
There’s also evidence that lifestyle modifications can make a big difference in dementia — a study published in February 2022 in The Lancet found that 12 modifiable risk factors, including hypertension, smoking, obesity, alcohol, physical activity, and diabetes, could account for 40 percent of dementia cases worldwide.
Additionally, the SOBA test detected oligomers in 11 people from the study’s control group. Upon studying the follow-up examination records, researchers found 10 of those people received diagnoses later in the life of either MCI or brain pathology consistent with Alzheimer’s disease.
“Based on the science, given what is known in the field about the order of events in the molecular biochemistry/pathology, we expect the amyloid beta toxic oligomers to be one of the earliest triggers of the disease, prior to fibril and plaque formation and
“[We] were hoping that our assay would detect toxic oligomers in presymptomatic individuals, but nonetheless we were surprised — and pleased — when it worked,” she added.
Test Can Accurately Predict Who Currents Has AD and Who May Develop It Later
According to researchers, the early “seeds” in the brain that later “grow” into Alzheimer’s disease are called amyloid beta proteins. Instead of behaving like healthy proteins in the brain, these amyloid beta proteins misfold and clump together, forming small masses called oligomers.
For reasons that are still not completely understood by scientists, the oligomers are thought to cause the damage that eventually results in Alzheimer’s.
Researchers found that SOBA (soluble oligomer binding assay) — could detect oligomers in the blood of patients with Alzheimer’s disease. In the control group, which only included people who showed no signs of cognitive impairment at the time their blood samples were taken, 11 people were found to have oligomers.
Ten of those people were able to be medically followed, and all were eventually diagnosed with mild cognitive impairment (MCI) or brain pathology consistent with Alzheimer’s. The test had identified the at-risk individuals before the presence of any symptoms, and the blood samples from people who never went on to develop cognitive impairment lacked the toxic oligomers.
Mild cognitive impairment is an early stage of memory or cognitive ability loss. People with MCI are at a significantly increased risk of developing dementia, but some people with MCI remain stable for many years, per Mayo Clinic.
How quickly might the SOBA laboratory test be available for doctors and patients to use?
Dr. Daggett reported the SOBA-AD version of the assay had been granted
“At AltPep we are working on our Alzheimer’s disease therapeutic, which is designed to bind the toxic oligomers, neutralize them, and stimulate their clearance,” she added. “In addition, we plan to pursue Breakthrough Status for our Parkinson’s disease/Lewy body dementia test in plasma.”
“At the University of Washington, my lab is funded by the National Institute of Aging and we are doing basic research to characterize and understand the role of toxic oligomers,” Dr. Daggett continued. “In addition, we work on a number of unrelated amyloid diseases, which is what allowed us to first discover the alpha-sheet structure targeted by SOBA and formed by unrelated amyloid disease-associated peptides and proteins.”
Test Results Were Confirmed Via Autopsy
SOBA uses a special synthetic test surface that’s able to bind with proteins in the blood, thereby allowing it to be tested for the presence of the toxic oligomers.
In another evaluation of the test, investigators used the test on blood samples from 310 research subjects who had previously made their blood samples and some of their medical records available for Alzheimer’s research. At the time the blood samples had been taken, the participants showed no signs of cognitive impairment, mild cognitive impairment, Alzheimer’s disease, or another form of dementia.
SOBA detected oligomers in the blood of individuals with mild cognitive impairment and moderate to severe Alzheimer’s. Researchers were able to examine the brains via autopsy in 53 cases after a participant died, and in 52 of those cases, the blood samples which had been taken years before their deaths contained toxic oligomers.
“It appears to accurately predict risk of cognitive decline in cognitively normal individuals and accurately separates Alzheimer from other neurodegenerative diseases,” says Sadowski.
Medical News Today also spoke with Dr. David A. Merrill, a psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA, about this study.
He stated this is important work in providing new options for early diagnosis and detecting Alzheimer’s disease before symptoms begin.
“When patients haven’t yet started to have memory loss, that’s the best point in time to intervene to prevent memory loss from occurring,” Dr. Merrill explained. “With a typical clinical diagnosis of Alzheimer’s disease, once somebody’s already symptomatic it may be too late to prevent significantly impairing memory loss. Studies in years past have shown with a clinical diagnosis of Alzheimer’s, up to 90% of the memory cells in the brain have already died.”
For the next steps in this research, he said he would like to see further validation of the test on a larger sample across all stages of the disease, from pre-symptomatic to mild cognitive impairment to more severe forms of the disorder that are already developed.
“It would also be interesting to see if any available
“It’s been controversial that amyloid might be a bystander in Alzheimer’s — it may not be the root cause of the memory loss or the death of brain cells,” he added. “So whether or not you remove the oligomers or the amyloid, it’s still a question of whether or not that will prevent memory loss or improve memory loss in those who have developed it, so it’s a really challenging disease.”
Researchers Hope to Make Test Widely Affordable and Widely Available
Daggett’s team is working with scientists at AltPep, a UW spinout company, to develop SOBA into a diagnostic test for oligomers.
“We want something that can give us a readout of what’s going on in the brain without having to do a lumbar puncture or expensive imaging, which is what’s done now (to diagnose AD) in the best of cases,” says Daggett.
SOBA requires a general simple blood test that could inexpensively available at most labs — even in a doctor’s office — as opposed to requiring very fancy technology and processing, she says. The costs for those procedures can be between $5,000 and $8,000 dollars, she adds.
“Also, SOBA appears to be much more sensitive and specific — so much more accurate than the other testing methods,” says Daggett.
These newly published findings are just the start, she says. “We’ve also evaluated samples from two other cohorts and are getting other samples and will continue to do so — that’s needed to validate what we’re finding,” says Daggett.
Sadowski agrees that the sample of preclinical patients in this study is relatively low. The test should be validated on a larger group of preclinical patients who need to be thoroughly characterized using Alzheimer’s imaging biomarkers like positron emission tomography (PET) scans, he says.
SOBA Could Be Used to Identify Other Diseases, Such as Parkinson’s Disease and Type 2 Diabetes
“The FDA has approved our breakthrough status application to develop this test,” says Daggett.
Researchers believe the test has further potential — in principle, this same technology can be used to detect other amyloid diseases. “Not just Alzheimer’s, but also Parkinson’s disease, type 2 diabetes, and more. The hope is that this method can help in diagnosing and studying many other ‘protein misfolding’ diseases,” says Daggett.
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